Solid oral form provided with a double release profile

Abstract

The present invention relates to a solid form, intended for the administration by oral route of at least one active ingredient and capable of guaranteeing a double release mechanism of said active ingredient, the first being determined by time and the second being determined by the pH, characterized in that said active ingredient is present there in the form of a microparticle system the microparticles of which possess a core formed wholly or partly by said active ingredient and coated with at least one layer determining said release profile of said active ingredient and formed by a material composed at least (i) 25 to 75% by weight relative to the total weight of said coating of at least one polymer A which is insoluble in the gastro-intestinal fluids, (ii) 25 to 75% by weight relative to the total weight of said coating of at least one polymer B possessing a solubilization pH value comprised within the pH range from 5 to 7, and (iii) 0 to 25% by weight relative to the total weight of said coating of at least one plasticizer, said polymers A and B being present in a polymer(s) B/polymer(s) A weight ratio at least equal to 0.25 It moreover relates to a method for the preparation of this solid form and of the corresponding microparticles.

1 . Solid form, intended for the administration by oral route of at least one active ingredient and capable of guaranteeing a double release mechanism of said active ingredient, the first being determined by time and the second being determined by pH, characterized in that said active ingredient is present there in the form of a microparticle system the microparticles of which possess a core formed wholly or partly by said active ingredient and coated with at least one layer determining said release profile of said active ingredient and formed by a material made up of at least:
 25 to 75% by weight relative to the total weight of said coating of at least one polymer A which is insoluble in the gastro-intestinal fluids,   25 to 75% by weight relative to the total weight of said coating of at least one polymer B possessing a solubilization pH value comprised within the pH range from 5 to 7, and   0 to 25% by weight relative to the total weight of said coating of at least one plasticizer,   
     said polymers A and B being present in a polymer(s) B/polymer(s) A weight ratio at least equal to 0.25. 
   
   
       2 . Solid form according to  claim 1 , possessing a modified three-phase release profile. 
   
   
       3 . Solid form according to  claim 1  or  2 , characterized in that it is presented in a matrix form within which said microparticles are dispersed. 
   
   
       4 . Solid form according to  claim 1 ,  2  or  3 , characterized in that it is a tablet. 
   
   
       5 . Solid form according to any one of the previous claims, in which the polymer A is chosen from ethylcellulose, cellulose acetate butyrate, cellulose acetate, type “A” or type “B” ammonio (meth)acrylate copolymers, poly(meth)acrylic acid esters, and mixtures thereof. 
   
   
       6 . Solid form according to any one of the previous claims, in which the coating of the microparticles contains 25% to 60% by weight, in particular 25 to 55% by weight and more particularly 30 to 50% of polymer(s) A relative to its total weight. 
   
   
       7 . Solid form according to any one of the previous claims, in which the polymer B is chosen from the methacrylic acid and methyl methacrylate copolymer(s), the methacrylic acid and ethyl acrylate copolymer(s), cellulosic derivatives such as cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellilate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, shellac gum, polyvinyl acetate phthalate, and mixtures thereof. 
   
   
       8 . Solid form according to any one of the previous claims, in which the coating of the microparticles contains 30to 75% by weight, in particular 35 to 70% by weight, in particular 40% to 60% by weight of polymer(s) B relative to its total weight. 
   
   
       9 . Solid form according to any one of the previous claims, in which the coating of the microparticles is formed by at least one mixture of ethylcellulose, cellulose acetate butyrate or type “A” or “B” ammonio (meth)acrylate copolymer with at least one methacrylic acid and ethyl acrylate copolymer or a methacrylic acid and methyl methacrylate copolymer or a mixture thereof. 
   
   
       10 . Solid form according to any one of the previous claims, in which the coating comprises the polymers A and B in a polymer(s) B/polymer(s) A weight ratio greater than or equal to 0.3, in particular greater than or equal to 0.4, in particular greater than or equal to 0.5, or even advantageously greater than or equal to 0.75. 
   
   
       11 . Solid form according to any one of the previous claims, in which the coating of the microparticles comprises moreover at least one plasticizer. 
   
   
       12 . Solid form according to the previous claim, in which the coating of the microparticles comprises less than 25% by weight, in particular 1% to 20% by weight, and more preferably 5% to 20% by weight of plasticizer(s) relative to its total weight. 
   
   
       13 . Solid form according to any one of the previous claims, in which the coating of the microparticles is composed of a single layer formed by said material. 
   
   
       14 . Solid form according to any one of the previous claims, in which the coating arranged on the surface of the microparticles is present at a coating level varying from 3 to 85% by weight, in particular 5 to 60% by weight, in particular 10 to 50%, or even 10to 40%, and more particularly 20 to 40% by weight of coating, relative to the total weight of said microparticle. 
   
   
       15 . Solid form according to any one of the previous claims, in which the coating arranged on the surface of the microparticles is obtained by the spraying in a fluidized bed, of a solution containing at least said polymers A and B in the solute state onto particles of active ingredient(s). 
   
   
       16 . Solid form according to any one of the previous claims, in which the microparticles possess an average diameter less than or equal to 2000 μm, in particular less than or equal to 1000 μm, in particular less than 800 μm, in particular less than 600 μm, or even less than 500 μm. 
   
   
       17 . Solid form according to any one of the previous claims, in which the active ingredient is chosen from the anaesthetics, analgesics, antiasthmatics, allergy treatment agents, the antineoplastics, anti-inflammatories, anticoagulants and antithrombotics, anti-convulsants, antiepileptics, antidiabetics, antiemetics, antiglaucoma agents, antihistaminics, anti-infective agents, in particular antibiotics, antifungals, antivirals, antiparkinsonians, anti-cholinergics, antitussives, carbonic anhydrase inhibitors, cardiovascular agents, in particular the lipopenics, anti-arrhythmic agents, vasodilators, anti-anginal drugs, anti-hypertensives, vasoprotectives and cholinesterase inhibitors, agents for treating disorders of the central nervous system, stimulants of the central nervous system, contraceptives, fertility promoters, dopamine receptor agonists, agents for the treatment of endometriosis, agents for treating gastro-intestinal disorders, immunomodulators and immunosuppressors, agents for treating memory disorders, antimigraine drugs, myorelaxants, nucleoside analogues, agents for treating osteoporosis, parasympathomimetics, prostaglandins, psychotherapeutic agents such as sedatives, hypnotics, tranquillizers, neuroleptics, anxiolytics, psychostimulants and antidepressants, dermatological treatment agents, steroids and hormones, amphetamines, anorexigenics, non-analgesic pain relieving drugs, antiepileptics, barbiturates, benzodiazepines, hypnotics, laxatives, psychotropic drugs. 
   
   
       18 . Solid form according to any one of the previous claims, comprising at least two types of microparticles differing from each other by distinct release profiles. 
   
   
       19 . Solid form according to any one of the previous claims, comprising at least two types of microparticles, in which said types differ from each other at least by the nature of the active ingredient that they contain and/or by the composition of their coating and/or the thickness of their coating. 
   
   
       20 . Method for the preparation of a solid form for the oral administration of at least one active ingredient according to any one of the previous claims, comprising at least stages involving:
 a) having microparticles formed wholly or partly by at least one active ingredient,   b) spraying in a fluidized bed onto the microparticles of stage a), a solution or dispersion containing at least one polymer A which is insoluble in the gastrointestinal fluids mixed with at least one polymer B possessing a solubilization pH value comprised within the pH range from 5 to 7, in a polymer(s) B/polymer(s) A weight ratio at least equal to 0.25,   c) mixing the microparticles of coated active ingredients obtained at the end of stage b) with one or more physiologically acceptable excipients capable of forming a matrix   d) agglomerating the mixture formed in stage c) by compression.   
   
   
       21 . Method according to the previous claim, in which the polymers A and B are as defined in  claims 5  to  10 . 
   
   
       22 . Method according to  claim 20  or  21  in which the microparticles obtained at the end of stage b) are as defined in  claims 11  to  16 . 
   
   
       23 . Microparticles possessing a core formed wholly or partly by at least one active ingredient, said core being coated with at least one layer determining a double release mechanism of said active ingredient, the first being determined by time and the second being determined by the pH, and formed by a material made up of at least:
 25 to 75% by weight, in particular 25% to 60% and, still more preferably, 25 to 55% by weight, and still more particularly 30 to 50% relative to the total weight of said coating of at least one polymer A which is insoluble in the gastro-intestinal fluids and chosen from ethylcellulose, cellulose acetate butyrate, a type “A” or type “B” ammonio (meth)acrylate copolymer, poly(meth)acrylic acid esters and mixtures thereof, and   25 to 75% by weight, in particular 30 to 75%, in particular 35 to 70%, or even 40 to 60% by weight relative to the total weight of said coating of at least one polymer B possessing a solubilization pH value comprised within the pH range varying from 5 to 7 and chosen from a methacrylic acid and methyl methacrylate copolymer, a methacrylic acid and ethyl acrylate copolymer and mixtures thereof.   
   
   
       24 . Microparticles according to the previous claim, the coating of which is formed by at least one polymer B/polymer A pair chosen from the following pairs:
 methacrylic acid and ethyl acrylate, 1:1 copolymer/ethylcellulose,   methacrylic acid and methyl methacrylate 1:2 copolymer/ethylcellulose,   mixture of methacrylic acid and ethyl acrylate 1:1 copolymer and methacrylic acid and methyl methacrylate, 1:2 copolymer/ethylcellulose,   methacrylic acid and ethyl acrylate 1:1 copolymer/cellulose acetate butyrate,   methacrylic acid and methyl methacrylate 1:2 copolymer/cellulose acetate butyrate,   mixture of methacrylic acid and ethyl acrylate 1:1 copolymer and methacrylic acid and methyl methacrylate 1:2 copolymer/cellulose acetate butyrate,   methacrylic acid and ethyl acrylate copolymer 1:1 copolymer/type “A” or type “B” ammonio (meth)acrylate,   methacrylic acid and methyl methacrylate 1:2 copolymer/type “A” or type “B” ammonio (meth)acrylate copolymer,   mixture of methacrylic acid and ethyl acrylate 1:1 copolymer and methacrylic acid and methyl methacrylate 1:2 copolymer/type “A” or type “B” ammonio (meth)acrylate copolymer.